Identification of a nucleoside analog active against adenosine kinase-expressing plasma cell malignancies.

Identification of a nucleoside analog active against adenosine kinase-expressing plasma cell malignancies. J Clin Invest. 2017 May 15;: Authors: Nayar U, Sadek J, Reichel J, Hernandez-Hopkins D, Akar G, Barelli PJ, Sahai MA, Zhou H, Totonchy J, Jayabalan D, Niesvizky R, Guasparri I, Hassane D, Liu Y, Sei S, Shoemaker RH, Warren JD, Elemento O, Kaye KM, Cesarman E Abstract Primary effusion lymphoma (PEL) is a largely incurable malignancy of B cell origin with plasmacytic differentiation. Here, we report the identification of a highly effective inhibitor of PEL. This compound, 6-ethylthioinosine (6-ETI), is a nucleoside analog with toxicity to PEL in vitro and in vivo, but not to other lymphoma cell lines tested. We developed and performed resistome analysis, an unbiased approach based on RNA sequencing of resistant subclones, to discover the molecular mechanisms of sensitivity. We found different adenosine kinase-inactivating (ADK-inactivating) alterations in all resistant clones and determined that ADK is required to phosphorylate and activate 6-ETI. Further, we observed that 6-ETI induces ATP depletion and cell death accompanied by S phase arrest and DNA damage only in ADK-expressing cells. Immunohistochemistry for ADK served as a biomarker approach to identify 6-ETI-sensitive tumors, which we documented for other lymphoid malignancies with plasmacytic features. Notably, multiple myeloma (MM) expresses high levels of ADK, and 6-ETI ...
Source: Clinical Lymphoma and Myeloma - Category: Cancer & Oncology Authors: Tags: J Clin Invest Source Type: research